Understanding the molecular basis of intrinsic radioresistance is fundamental to the design of effective radiotherapy protocols. The goal of this project is to investigate the contribution of oncogenes to tumor radioresistance in pursuit of identifying sensitive target(s) for pharmacological intervention. The major observations are: 1. Oncogenes and Radioresistance. Altered expression of the ras gene family, resulting from either missense mutations or transcriptional activation, has been implicated in intrinsic resistance to ionizing radiation. Using ras-transformed mouse and human tumor cell lines we demonstrated: (a) dosage-dependent correlation between the amounts of ras-encoded protein, p2l(ras), and radioresistance; (b) the effect on radiation response is independent of neoplastic transformation by ras; and, (c) localization of p2l(ras) to the inner side of the plasma membrane is critical for maintenance of the radioresistant phenotype. 2. p21(ras) As a Therapeutic Target. Cellular p2l is subject to a series of posttranslational modifications, of which isoprenylation is obligatory for its membrane localization and biological activity. Biosynthesis of the required isoprenoids is part of the mevalonate pathway of cholesterol biosynthesis; the early and rate-limiting step is conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) into mevalonate, catalyzed by HMG-CoA reductase. Our studies indicate that inhibitors of HMG-CoA reductase, including lovastatin and limonene, prevent p2l(ras) attachment to the cell membrane with subsequent reduction in tumor radioresistance. Lovastatin and limonene are prototype inhibitors of HMG-CoA reductase suitable for clinical use. Such drugs are of particular interest since they might suppress tumor growth in vivo and increase the efficacy of radiotherapy.